Background. Evidence has accumulated that 1,25- dihydroxyvitamin D3 [1,25-(OH)2D3] is involved in the regulation of the proliferation of breast tumor cells. For complete tumor suppression high hypercalcemic doses of 1,25-(OH)2D3 are needed. The aim of this study was to assess the effect of combined treatment of 1,25- (OH)2D3 at low doses and melatonin (MEL) on the proliferation of estrogen-responsive rat breast cancer cell line RM4. Materials and methods. RM4 cell proliferation was assessed by [3H]thymidine uptake. The presence of TGF-beta 1 in serum-free conditioned medium was determined by inhibition antibody binding assay. Results. In 17-beta E cultured RM4 cells both MEL and 1,25-(OH)2D3 alone and in combination significantly reduced [3H]thymidine incorporation in a doserelated fashion. MEL by itself was ineffective in inhibiting the FCS-cultured RM4 cells, while 1,25-(OH)2D3 strongly inhibited [3H]thymidine incorporation. Meanwhile, MEL increased the sensitivity of the FCS cultured RM4 cells to 1,25-(OH)2D3 in the combined regimen, from 20- to 100-fold. MEL significantly enhanced the TGF-beta1 secretion from RM4 cells and vitamin D3 increased the TGF-beta1 secretion in a dose dependent manner, from 2- to 7-fold. Moreover, a further enhancement of the TGF-beta1 release was obtained with the combined treatment, but only for low 1,25-(OH)2D3 concentrations. The addition of monoclonal anti-TGF-beta1 antibody to the medium of RM4 cells exposed to vitamin D3 alone or in combination with MEL increased the [3H]-thymidine uptake compared to the correspondent cells cultured without antibody.Our data point to a potential benefit of combination therapy with 1,25-(OH)2D3 and MEL in the treatment of breast cancer and suggest that the growth inhibition could be related, at least in part, to the enhanced TGF-beta-1 secretion.
Melatonin and vitamin D-3 increase TGF-Beta 1 release and induce growth inhibition in breast cancer cell cultures / Bizzarri, Mariano; Cucina, Alessandra; VALENTE M., G; Tagliaferri, F; Borrelli, V; Stipa, F; Cavallaro, Antonino. - In: JOURNAL OF SURGICAL RESEARCH. - ISSN 0022-4804. - STAMPA. - 110(2003), pp. 332-337. [10.1016/S0022-4804(03)00040-4]